The differentiation of naïve CD4+ T-cells into Thelper (Th) cells is a central process that plays a crucial and determinant role in directing the type of immune responses that develop against pathogenic and non-self antigens in humans. There are two principal types of immune response, namely type-1 (Th1) and type-2 (Th2), which are categorized on the basis of the cytokine profiles that these responses produce and by the class of Th cells which contribute to the immune response.
Th1 cells secrete mainly interleukin-2 (IL-2), interferon-gamma (IFN-γ), granular macrophage-colony stimulating factor (GM-CSF), and tumour necrosis factor-alpha (TNF-α). These cytokines are the essential factors for the initiation of cell-mediated immunities that involve the activation of cytotoxic CD8+ T-cells, natural killer (NK) cells, monocytes and macrophages. Th1 immunity also involves the direct activation of naïve CD8+ Tcytotoxic-cells (Tc) by signalling through T-cell receptors (TCR), which in turn recognize non-self or pathogenic antigens presented by major histocompatibility complex class I (MHC-I) on antigen-presenting cells (APC). Once they are activated, naïve CD8+ Tc-cells differentiate into long-term Tc-effector and Tc-memory cells, which carry out the cytotoxic killing of pathogens.
Th2 cells produce mainly IL-4, IL-5, IL-10 and IL-13 that are primarily involved in the initiation of humoral immune responses.
The differentiation of naïve CD4+ Th-cells is initiated when their TCR encounters and locks on to an antigen bound to the MHC-class II (MHC-II) on an APC. In conjunction with the activation of co-stimulatory pathways, stimulation of the TCR delivers a signal which is mediated through the activation of the protein kinase C (PKC) pathway, that in turn promotes the differentiation of naïve CD4+ T-cells into Th-progenitor cells. At this stage of differentiation, progenitor Th-cells have the capability to differentiate into either Th1 or Th2 cells, depending on the cytokine environment. Upon exposure to IL-12, IL-18, IL-23, IL-27 or IFN-γ, Th-progenitor cells are driven toward the Th1 lineage commitment, whereas in the presence of IL-4 or IL-10, the Th-progenitor cells are programmed to develop into Th2 lineage.
It is also significant to note that Th1 and Th2 cytokines have a cross-inhibitory action on each other. This regulatory interaction between Th1 and Th2 signals appears to act as a mechanism to shift the balance toward a particular lineage commitment.
Appropriate induction of Th1 immunity is essential for fighting infection by invading bacterial and viral pathogens. The production of Th1 cytokines plays a crucial role in the function of Th1 immunity as a mechanism to fight pathogens and also to participate in tumour surveillance.
Several transcription factors have been identified as important regulators of Th1 lineage development. These include STAT-1, STAT-4, NF-kB, IRF-1, T-bet (or Tbx21) and members of the Ets family.
However, excessive production of Th1 cytokines has been associated with autoimmune diseases. Th1 immunity is also a key mediator of the ‘cytokine storm’ that often causes fatality in severe cases of infectious diseases such as pneumonia and ‘bird flu’. The mechanisms of the pathogenesis of autoimmune diseases and inflammatory conditions involves the production of Th1 cytokines, activation and recruitment of CD4+ Th cells, CD8+ Tc cells, natural killer (NK) cells and other components of the immune system such as macrophages. Accordingly, elevated expression of T-bet and Th1-cytokines are central to mediating the pathological processes of many autoimmune diseases, acute and chronic inflammatory conditions, solid organ transplant rejection, graft-versus-host disease in bone marrow transplantation, rejection of embryo implantation after IVF and a range of other diseases and pathologies.
There are a number of immuno-suppressive/anti-inflammatory agents and different therapies currently used for Th1-related diseases and organ transplantation in the clinic as well as showing promising therapeutic potential in pre-clinical stage. These include steroid hormones and their analogues (estrogen, progesterone, human growth hormones, glucocorticoids, dexamethasone), small chemical molecules, non-steroidal anti-inflammatory drugs (NSAIDs), cyclosporine, rapamycin, sulfasalazine, methotrexate, calcineurin inhibitors, COX-2 inhibitors, antibodies against specific cytokines and their receptors (anti-TNFα antibody [Infliximab], anti-costimulatory molecule antibody, anti IL-2 receptor antibody [Daclizumab], anti-IL12 antibody). However, there are a number of problems with the use of these immuno-suppressive drugs.
Firstly, these drugs have significant side-effects that particularly associated with chronic use. For example, nephrotoxicity is associated with calcineurin inhibitors, hypertension and cardiovascular diseases with the use of corticosteroids. There is a significantly increased risk of breast cancer and ovarian cancer from the use of steroid hormones, an increased risk of development of haematologic neoplasms and kidney problems with chronic use of infliximab, and cytotoxicity with the use of methotrexate and rapamycin.
Secondly, there are major concerns and problems over long-term graft survival and chronic graft rejection with prolonged exposure to these drugs. This is evidenced by the fact that although the use of immuno-suppressive drugs improves 1-year graft survival from 45% to about 80-90% for most organ transplants, long-term graft survival (5 years or more) has changed little, remaining at around 50-60%. Another example is the use of cyclosporine in the prevention of graft-versus-host disease in bone marrow transplantation. Its use is highly effective in the clinical setting. However, patients often relapse due to the inhibitory action of cyclosporine on the graft-versus-leukaemia action by the donor marrow. There are also cytotoxic effects and a risk of renal damage associated with chronic use of cyclosporine. This compromises the clinical benefit of bone marrow transplantation in leukaemia patients. Also, these immuno-suppressive drugs have to be administered regularly and over a prolonged period of time.
Intra-venous injection of pooled serum immunoglobulins, also known as intra-gam, from thousands of volunteers has also been used to treat a wide range of immune-related disorders. However, this treatment requires a large pool of serum, in the order of tens of thousand of donors, with the isolation of serum immunoglobulins being an inefficient and costly process. Since immunoglobulins used in such treatments are isolated from human serum, there are also risks of transmission of diseases from donors to patients. Thus, the clinical benefits and the cost effectiveness of such treatments remain limited.
Hence, there remains a requirement for new approaches to the treatment of autoimmune diseases, inflammatory diseases and allergy-related diseases.